The trial, registered under numbers NL6179 and NTR6326, was designed as a prospective non-randomised cluster study and enrolled one hundred adults between July 2018 and June 2023. Rather than randomising individual patients, the investigators assigned whole institutions to different care models: the University Medical Centre Groningen, a tertiary referral centre, delivered a structured goal-directed nutritional support protocol known as GDNS, while the Hospital Group Twente, a secondary hospital, provided usual care. This cluster design was chosen deliberately to minimise the risk that the intervention protocol would contaminate routine practice at a single site. Eligible patients were over eighteen years old, had histologically confirmed, previously untreated oesophageal cancer, and were scheduled for curative-intent chemoradiotherapy and surgery. Patients undergoing salvage oesophagectomy, those with cervical lymph node involvement or distant metastases, post-cricoid tumours, poor performance status, or an inability to complete questionnaires were excluded. Fifty patients were included in each arm.

The intervention itself was built on three technical pillars. First, each patient in the GDNS group was assigned a dedicated dietitian acting as a case manager, who monitored dietary intake continuously and performed all nutritional assessments from baseline onward. Second, energy requirements were measured rather than merely estimated: indirect calorimetry was performed in 88 percent of patients at baseline, complementing standard predictive equations, alongside the Patient Generated-Subjective Global Assessment. Third, nutritional support—oral nutritional supplements, enteral tube feeding, and parenteral nutrition where necessary—was provided proactively rather than reactively. Usual care, by contrast, involved dietitians at multiple locations who monitored weight and intake during chemoradiotherapy and initiated support when deemed necessary, with research nurses conducting assessments using the short form of the PG-SGA, but without routine recording of intake or measured energy expenditure.

The study’s primary endpoint was the change in appendicular skeletal muscle index, or ASMI, the mass of limb skeletal muscle normalised to squared height, expressed in kilograms per square metre. Because computed tomography, the reference standard for muscle quantification, was only systematically available in the intervention group, the researchers relied on bioelectrical impedance analysis using a Seca mBCA 525 device, applying Sergi’s validated prediction formula and cross-checking the estimates against two independent biomarkers: skeletal muscle area measured on abdominal CT scans at the third lumbar vertebra level, and urinary creatinine excretion from 24-hour collections. The correlations were convincing—bioelectrical ASMI tracked CT-derived skeletal muscle index with correlation coefficients rising from 0.48 at baseline to 0.96 at twelve months, and urinary creatinine correlated at 0.58 and 0.72 at baseline and one year, respectively. Measurements were taken at seven or more timepoints: baseline, one week and three to six weeks after the start of chemoradiotherapy, between radiation completion and surgery, at oesophagectomy, before discharge, and at three, six, and twelve months postoperatively.

The central finding is a distinctive decline-recovery-decline pattern in muscle mass that played out identically in shape across both groups. During chemoradiotherapy, ASMI fell by 2.53 percent in the GDNS group and 3.20 percent under usual care—a modest loss compared with the pooled figure of roughly minus 6.69 percent reported in meta-analyses of neoadjuvant therapy. Between the end of radiotherapy and surgery, muscle mass actually rebounded in both arms, gaining 0.95 percent with GDNS and 2.51 percent with usual care, consistent with a recovery window that prior prehabilitation research has also documented. Then, after oesophagectomy, the pattern reversed: by twelve months, ASMI had fallen by 5.75 percent in the intervention group and 7.09 percent under usual care. Notably, in the peri-operative window alone—the stretch from the preoperative visit to early recovery—the usual care group lost 4.88 percent of limb muscle while the GDNS group lost only 0.93 percent, the sole between-group comparison that reached nominal statistical significance (P = 0.038), although this signal dissolved after adjustment for confounders such as surgical duration, blood loss, and hospital stay.

Formal statistical modelling reinforced the picture of a real but statistically non-significant difference favouring the intervention. An analysis of covariance incorporating sex, age, smoking, body mass index, and complications found no significant between-group difference in relative ASMI change at any phase, and sensitivity analyses adding sepsis to the covariates confirmed the result. Generalised linear mixed-effects modelling, which best captured the non-linear trajectory with a random-intercept model containing a quadratic time term over a mean seventeen-week interval from baseline to surgery, likewise detected no intervention effect. The investigators had powered the study to detect a five percent improvement in muscle mass during chemoradiotherapy; the observed differences, though directionally consistent, fell short of that threshold. Reduced sample size—driven partly by attrition, with only 16 and 21 patients respectively completing the full twelve-month follow-up, and by the logistical strains of conducting research during the COVID-19 pandemic—likely constrained the study’s ability to confirm what the trends suggest.

Beyond the primary endpoint, the goal-directed approach left clearer fingerprints on other measures of nutritional status. Energy intake in the GDNS group rose from 23.4 to 28.0 kcal/kg and protein intake from 1.03 to 1.32 g/kg during chemoradiotherapy, values that closely match international ESPEN guideline targets of 25 to 30 kcal/kg and at least 1.0 to 1.5 g protein/kg. Body mass index declined less steeply during radiotherapy in the intervention group, and while waist circumference and fat mass index increased slightly under GDNS, they decreased under usual care. Urinary creatinine, a biochemical surrogate of total muscle mass, remained stable in the intervention group across the first six months but declined significantly under usual care—a between-group difference that did reach significance. Malnutrition defined by the GLIM criteria nonetheless rose in both arms during chemoradiotherapy, from 34.1 to 58.5 percent in GDNS and from 35.4 to a striking 85.4 percent under usual care, and quality of life, assessed with the EORTC QLQ-C30 questionnaire, was significantly better at the end of radiotherapy in the intervention group before recovering in both arms after surgery.

The study also surfaced uncomfortable truths about translating measured physiology into clinical targets. Although indirect calorimetry revealed that measured resting energy expenditure at baseline—1854 kcal on average—significantly exceeded the 1674 kcal predicted by standard equations, the measured targets were actually applied in clinical practice in only 22 percent of cases at baseline and 37.5 percent later in treatment, apparently reflecting dietitians’ habitual reliance on predictive equations and a blanket 30 percent physical-activity correction that overlooks interindividual variation. Surgical outcomes added further complexity: the GDNS group experienced longer operations, greater blood loss, longer hospital stays, and a higher rate of postoperative sepsis (19.4 versus 2.6 percent), which the authors attribute plausibly to a learning curve, since robot-assisted oesophagectomy was being introduced at the tertiary centre during the study while the secondary hospital had already mastered it. One-year overall and disease-free survival did not differ between the arms.

Set against the wider literature, the modest muscle loss observed in this trial is itself noteworthy. Previous cohorts of oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy have reported substantially larger declines, and the present figures are more comparable to those seen with neoadjuvant chemotherapy alone, hinting that both intensive support and improving usual care may contribute to attenuation. The findings also echo the growing consensus that nutrition alone cannot fully protect muscle: the PERFECT exercise trial found that resistance training preserved fat-free mass after oesophagectomy but was thwarted by inadequate postoperative protein intake, exactly the deficit the Dutch team observed between three and six months after surgery in their intervention group. The authors argue that this points squarely toward personalised, integrated interventions combining dietetics and physical therapy, with particular attention to the postoperative phase, where the steepest losses occurred in both arms.

Ultimately, the study delivers a measured verdict. A dedicated dietitian, calorimetry-based targets, and proactive tube feeding and supplementation produced better nutritional intake, more favourable body composition trends, and improved quality of life, and smaller—but not statistically significant—muscle loss during chemoradiotherapy and at one year after surgery. Survival was unchanged, and unexpected surgical complications in the intervention cohort cloud the risk-benefit calculus. What the trial establishes most firmly is the biological narrative: muscle mass in oesophageal cancer follows a predictable rhythm of loss during radiation, partial recovery before surgery, and renewed decline afterward, and the postoperative period is where the greatest opportunity for intervention still lies. For clinicians managing this notoriously catabolic disease, the message is that even intensive nutrition cannot be a substitute for a genuinely integrated, individualised recovery strategy.

Drawing attention to the various types of prehabilitation, the researchers found significant benefits stemming from exercise interventions, nutritional enhancements, psychological support, and cognitive training. Among these, physical exercise emerged as the most effective component, underscoring the vital role that fitness plays in recovery. Dr. McIsaac emphasized the importance of patients inquiring about prehabilitation as a preparatory measure before elective surgeries. He suggests that increasing physical activity and protein intake in the weeks leading up to surgery can markedly shorten the post-operative recovery period for patients.

Despite its potential, Dr. McIsaac cautioned that much of the prehabilitation research has been conducted in singular hospital environments, raising concerns about the applicability of these findings across various healthcare systems. He noted, “Prehabilitation is very promising, but we still don’t know how best to implement it across hospitals and health systems.” The study underscores a crucial question in modern surgical care: How can healthcare systems effectively disseminate prehabilitation practices to benefit a broader range of surgical patients?

The historical roots of prehabilitation can be traced back to World War II, originally used by the British Army to improve the health and fitness of military recruits. Over the last three decades, this concept has evolved into an essential area of study within the medical community. Dr. McIsaac pointed out the established correlation between a patient’s physical fitness levels and their subsequent recovery from surgery. He argued passionately for the integration of prehab into standard pre-operative care. “While many patients express the desire to enhance their fitness levels before surgery, they often lack guidance on how to begin,” he stated. This gap in patient knowledge presents an opportunity for healthcare providers to establish a more supportive framework around prehabilitation.

As reported, over 300 million surgeries are performed globally each year, with more than 20% of patients experiencing post-operative complications that can prolong hospital stays and hinder recovery. Therefore, developing a robust prehabilitation protocol could play a crucial role in minimizing these adverse outcomes. The Ottawa Hospital is currently spearheading multi-center prehabilitation trials led by the Aging Innovation In Perioperative Medicine & Surgery (AIMS) Research Group. These trials are vital as they not only expand the patient pool but also enhance the generalizability of findings.

In what is considered an innovative approach, one of the ongoing trials focuses on virtual home-based prehabilitation, which is particularly relevant in today’s increasingly digital world. This trial is currently enrolling participants across Canada who have upcoming surgeries requiring at least one night in the hospital. Anyone interested in joining the trial can access information through designated recruitment materials.

A significant aspect of this research is the emphasis on patient involvement and engagement. Collaborative efforts with patient partners have been integrated into the study design to ensure that the trials reflect the needs and experiences of those who will be impacted most. Gurlie Kidd, a retired social worker who has undergone significant surgery herself, has been a valuable patient partner since 2020. Her insights have been pivotal in aligning the research objectives with patient expectations and realities, making the prehabilitation journey more relatable and accessible.

In the context of healthcare today, the integration of patient feedback into clinical research not only fosters trust between patients and healthcare providers but also empowers patients to take actionable steps toward improving their surgical outcomes. “It is very empowering to know that there’s something you can do to prepare for surgery that will help your recovery. Patients are hungry for this,” Kidd stated, underlining the critical role of patient advocacy in the research process.

With ongoing support from various organizations, including the Canadian Institutes of Health Research and The Ottawa Hospital, significant resources have been allocated to further explore the nuances of prehabilitation. This growing field of study could alter the landscape of surgical care and challenge traditional perspectives on how best to prepare patients for surgery.

As the healthcare community continues to investigate the implications of prehabilitation, it is essential to establish clear guidelines and protocols that can be applied across diverse healthcare settings. Such guidelines must account for different surgical procedures, patient demographics, and institutional capabilities to maximize the potential benefits of prehab for all surgical candidates.

In summary, the evidence gathered presents a compelling case for the broader incorporation of prehabilitation into surgical planning. Rather than viewing recovery as a passive process that begins after surgery, healthcare providers are encouraged to rethink their approach and actively engage patients in their pre-operative journey. By doing so, they may significantly enhance surgical recovery outcomes and reshape patient experiences in a more positive light.

Subject of Research: Prehabilitation in surgical patients
Article Title: Relative efficacy of prehabilitation interventions and their components: systematic review with network and component network meta-analyses of randomised controlled trials.
News Publication Date: January 22, 2025
Web References: BMJ Article
References: DOI: 10.1136/bmj-2024-081164
Image Credits: The Ottawa Hospital

Keywords: Prehabilitation, Surgery, Clinical Research, Physical Exercise, Patient Health.